Compositions for Ophthalmologic Devices

ABSTRACT

The present invention relates to borate and phosphate containing compositions, especially eye care compositions, achieving physiologically compatible pH and tonicity as well as good bacteriostatic properties. Methods of using the compositions of the present invention are also disclosed.

RELATED APPLICATIONS

The present application claims the benefit of U.S. provisional patentapplication 63/136,370, filed Jan. 12, 2021, the entirety of whichapplication is hereby incorporated by reference herein as if fully setforth herein.

FIELD OF TECHNOLOGY

The present invention relates to borate and phosphate containingcompositions, especially eye care compositions, achievingphysiologically compatible pH and tonicity as well as goodbacteriostatic properties. Methods of using the compositions of thepresent invention are also disclosed.

BACKGROUND OF THE INVENTION

Contact lenses are generally provided to consumers as individuallypackaged products. The single unit containers which package such contactlenses typically use buffered saline or deionized water as storage orpackaging solutions.

Such packaging solutions should provide for, at least in some cases, ashort-term period—e.g., between solution preparation and sterilizationof the end-staged packaged product—an environment that does notfacilitate the growth of harmful or undesirable microorganisms.Moreover, the packaging solutions should be gentle to the eye since atleast some of the packaging solution will, most likely, remain on acontact lens once it is removed from the packaging solution and placeddirectly on (i.e., by direct application to) the eye.

The contact lens (or other ophthalmic device) packaging solution shouldalso be compatible with the materials forming the contact lens (or otherophthalmic device).

A challenge in preparing packaging solutions for ophthalmic devices isformulating solutions which do not negatively affect eye comfort or thesolution's compatibility with the material(s) forming the ophthalmicdevice. One important component of ophthalmic compositions, includingpackaging solutions, is the buffer incorporated, which helps to maintainthe pH of the composition within an acceptable physiological range.

A benefit to using boric acid/borate as the buffer relates to its uniqueability to maintain formulation (to which it is added) pH nearphysiological pH (˜7) with a secondary impact of imparting at, lowconcentrations, bacteriostatic (as opposed to bactericidal)characteristics to formulations. Such “static” characteristics reducethe potential for eye irritation. Reduced concentrations of boricacid/borate, however, tend to also sacrifice its efficacy againstcertain microorganisms (e.g., Pseudomonas aeruginosa).

Phosphates are also known to be capable buffers, but, unfortunately,phosphates are also known promoters of microbial growth.

The present inventors have discovered that by appropriately combiningboric acid/borate and phosphate buffers, adequately buffered,bacteriostatic compositions (e.g., packaging solutions) can be achieved.More specifically, such buffered solutions can be achieved by combiningboric acid/borate with phosphates at specific ratios of boricacid/borate to phosphate buffers—as detailed below.

DESCRIPTION OF FIGURES

FIG. 1 is a graph showing microbial colony forming units (CFU) ofStaphylococcus aureus present at Day 0, 1 and 2 of challenge withcertain compositions of the present invention.

FIG. 2 is a graph showing microbial colony forming units (CFU) ofPseudomonas aeuroginosa present at Day 0, 1 and 2 of challenge withcertain compositions of the present invention.

FIG. 3 is a graph showing microbial colony forming units (CFU) ofEscherichia coli present at Day 0, 1 and 2 of challenge with certaincompositions of the present invention.

FIG. 4 is a graph showing microbial colony forming units (CFU) ofBacillus subtilis present at Day 0, 1 and 2 of challenge with certaincompositions of the present invention.

FIG. 5 is a graph showing microbial colony forming units (CFU) ofSalmonella typhimurium present at Day 0, 1 and 2 of challenge withcertain compositions of the present invention.

FIG. 6 is a graph showing microbial colony forming units (CFU) ofCandida albicans present at Day 0, 1 and 2 of challenge with certaincompositions of the present invention.

FIG. 7 is a graph showing microbial colony forming units (CFU) ofAspergillus brasilensis present at Day 0, 1 and 2 of challenge withcertain compositions of the present invention.

FIG. 8 is a graph showing microbial colony forming units (CFU) ofFusarium keratoplasticum present at Day 0, 1 and 2 of challenge withcertain compositions of the present invention.

FIG. 9 is a graph (Chart 9) presents a comparison of microorganismreduction percentage on each EXP buffer vs the Control Buffer.

FIG. 10 is a graph showing P. aeruginosa CFU/mL Recovery Counts (1350CFU/mL Day 0 Delivery Count in PBS) at Day 1, 2 and 3 of challenge witha certain composition of the present invention.

FIG. 11 is a graph showing P. aeruginosa Log reduction at Day 1, 2 and 3of challenge with a certain composition of the present invention.

FIG. 12 is a graph showing percent count reduction of P. aeruginosa atDay 3 of challenge with a certain composition of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to compositions, comprising:

-   -   a. from about 0.1% w/v to less than or equal to about 0.80% w/v        of a borate compound;    -   b. from about 0.3% w/v to about 0.9% w/v of a phosphate        compound; and    -   c. ophthalmologically acceptable carrier        wherein the concentration of the phosphate compound is at least        about 1.5 times the amount of the borate compound on weight        basis.

The present invention also relates to methods of making and using thedisclosed compositions.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, the present invention relates to compositionscomprising a borate compound and a phosphate compound as anophthalmologically acceptable carrier.

The compositions may be useful for storing or as a packaging solutionfor ophthalmic devices.

The compositions may be useful for direct application to the eyes for aneye care benefit such as relieving eye discomfort.

The compositions and methods of the present invention can comprise,consist of, or consist essentially of the steps, essential elements andlimitations of the invention described herein, as well any of theadditional or optional ingredients, components, or limitations describedherein. The term “comprising” (and its grammatical variations) as usedherein is used in the inclusive sense of “having” or “including” and notin the exclusive sense of “consisting only of.” The terms “a” and “the”as used herein are understood to encompass the plural as well as thesingular.

Unless otherwise indicated, all documents cited are, in relevant part,incorporated herein by reference; the citation of any document is not tobe construed as an admission that it is prior art with response to thepresent invention. Furthermore, all documents incorporated herein byreference are only incorporated herein to the extent that they are notinconsistent with this specification.

The present invention as disclosed herein may be practiced in theabsence of any compound or element (or group of compounds or elements)which is not specifically disclosed herein.

As used herein, “pharmaceutically acceptable” means biologicallytolerable, and otherwise biologically suitable for application orexposure to the eyes and surrounding tissues of the eyes without undueadverse effects such as toxicity, incompatibility, instability,irritation, allergic response and the like.

All percentages, parts and ratios are based upon the total weight of thecomposition of the present invention, unless otherwise specified. Allsuch weights as they pertain to the listed ingredients are based on theactive level and, therefore, do not include carriers or by-products thatmay be included in commercially available materials, unless otherwisespecified.

The Borate Compound

The compositions of the present invention comprise a borate. As usedherein, the term “borate” shall refer to boric acid, salts of boric acidand other pharmaceutically acceptable borates, or combinations thereof.Suitable borates include, but are not limited to, boric acid;pharmaceutically acceptable salts, such as alkaline metal salts such assodium borate, potassium borate; alkaline earth metal salts such ascalcium borate, magnesium borate; transition metal salts such asmanganese borate; and mixtures thereof.

The borate compound can be present in the compositions at concentrationsof from about 0.1%, preferably from about 0.2%, preferably from about0.25%, w/v to less than or equal to 0.80% (or about 0.80%), preferably0.7% (or about 0.7%), preferably 0.6% (or about 0.6%), preferably 0.5%(or about 0.5%), preferably 0.45% (or about 0.45%), preferably 0.4% (orabout 0.4%), preferably 0.35% (or about 0.35%), preferably 0.3% (orabout 0.3%), w/v, in each case, of the total composition. The boratecompound may be present in the compositions at concentrations of fromabout 0.1% w/v to less than or equal to 0.40% (or about 0.40%) w/v,preferably from about 0.2% w/v to less than or equal to 0.35% (or about0.35%) w/v, or preferably from about 0.25% w/v to less than or equal to0.30% (or about 0.30%) w/v of the total composition.

The Phosphate Compound

The compositions of the present invention comprise a phosphate compound.As used herein, the term “phosphate” shall refer to phosphoric acid,salts of phosphoric acid and other pharmaceutically acceptablephosphates, or combinations thereof. Suitable phosphates may beincorporated as one or more monobasic phosphates, dibasic phosphates andthe like. Examples of phosphate compounds useful in the compositions arethose selected from pharmaceutically acceptable phosphate salts ofalkali and/or alkaline earth metals. The phosphate compound may includeone or more of sodium dibasic phosphate (Na₂HPO₄), sodium monobasicphosphate (NaH₂PO₄), and potassium monobasic phosphate (KH₂PO₄).

The phosphate compound can be present in the compositions atconcentrations of from 0.3% (or about 0.3%) w/v to 0.9% (or about 0.9%)w/v, preferably from 0.4% (or about 0.4%) w/v to 0.85% (or about 0.85%)w/v, preferably from 0.5% (or about 0.5%) w/v to 0.8% (or about 0.8%)w/v or preferably from 0.6% (or about 0.6%) w/v to 0.75% (or about0.75%) w/v of the total composition.

The concentration of the phosphate compound may be at least 1.5 (orabout 1.5), preferably at least 2.0 (or about 2.0), and preferably atleast 2.5 (or about 2.5), but up to 4, preferably up to 3, times theamount of the borate compound on a weight basis.

The ratio of the phosphate compound to the borate compound may be from1.5:1 (or about 1.5:1) to 3:1 (or about 3:1) preferably from 2:1 (orabout 2:1) to 3:1 (or about 3:1) or preferably 2:1 (or about 2:1) on aweight basis.

An Ophthalmologically Acceptable Carrier

The compositions of the present invention comprise an ophthalmologicallyacceptable carrier. The ophthalmologically acceptable carrier may bewater or an aqueous excipient solution. The term “aqueous” typicallydenotes a formulation wherein the excipient is at least about 50%, morepreferably at least about 75% and in particular at least about 90% andup to about 95% or preferably about 99%, by weight, water. The water isdistilled water. The carrier may be free of Ci-4 alcohols such asmethanol, ethanol, propanol, isopropanol, butanol, and the like whichcan sting, irritate, or otherwise cause discomfort to the eye.

The water may be present in the ophthalmologically acceptable carrier atconcentrations of from about 96% to about 99.9%, preferably, from about98% to about 99.5%, or preferably, from about 99.0% to about 99.5% byweight of the total composition.

The ophthalmologically acceptable carrier may be present atconcentrations of from about 96% to about 99.5%, preferably, from about98% to about 99.5%, or preferably, from about 98.5% to about 99.2% byweight of the total composition.

The compositions may be sterile, namely such that the absence ofmicrobial contaminants in the product prior to release or use arestatistically demonstrated to the degree necessary for such products.The compositions may be selected to have no or substantially nodetrimental, negative, harmful effect on the contact lens being thereinor on the eye (or on the region around the eye).

The compositions according to the present invention are physiologicallycompatible with the eye and ophthalmic devices. Specifically, thecomposition should be “ophthalmologically safe” for use with anophthalmic device such as a contact lens, meaning that a contact lenstreated with the solution is generally suitable and safe for directplacement on or direct application to the eye without rinsing, that is,the solution is safe and comfortable for ophthalmic devices, of anyfrequency of application, wetted with the solution, including contactlenses of any wear frequency. An ophthalmologically safe composition hasa tonicity and pH that is compatible with the eye and includesmaterials, and amounts thereof, that are ophthalmically compatible andnon-cytotoxic according to ISO standards and U.S. Food & DrugAdministration (FDA) regulations.

The compositions of the present invention may be adjusted with tonicityagents, to approximate the osmotic pressure of normal lacrimal fluids,which is equivalent to a 0.9 percent solution of sodium chloride or 2.5percent of glycerol solution. The compositions may be made substantiallyisotonic with physiological saline used alone or in combination withother tonicity agents such as glycerol, otherwise if simply blended withsterile water and made hypotonic or made hypertonic the ophthalmicdevices such as contact lenses may lose their desirable opticalparameters. Correspondingly, excess saline may result in the formationof a hypertonic composition, which will cause stinging, and eyeirritation. The osmolality of the composition may be at least about 200mOsm/kg, preferably from about 200 to about 450 mOsm/kg, preferably fromabout 205 to about 380 mOsm/kg, preferably from about 210 to about 360milliosmoles per kilogram (mOsm/kg), preferably from about 250 to about350 mOsm/kg, or, preferably, from about 300 to about 330 mOsm/kg. Theophthalmic compositions will generally be formulated as sterile aqueouscompositions.

Examples of suitable tonicity adjusting agents include, but are notlimited to, glycerin, sodium, potassium, calcium, zinc and magnesiumchloride, alkali metal halides, dextrose, and the like and mixturesthereof. These agents may be used individually in amounts ranging fromabout 0.01 to about 2.5% w/v and preferably from about 0.2 to about 1.5%w/v.

The tonicity adjusting agent may be sodium chloride which can beincorporated at concentrations of from about 0.4 to about 0.9,preferably, from about 0.4 to about 0.7, or preferably, from about 0.5%to about 0.6% by weight of the total composition.

The compositions of the present invention may have a pH of from about5.0 to a pH of about 8.0, preferably a pH of from about 6.5 to a pH ofabout 8.0, preferably a pH of from about 6.5 to a pH of about 7.5,preferably a pH of about 7. Compositions (as noted above) may preferablyhave a pH matching the physiological pH of the human tissue to which thecomposition will contact or be directly applied.

The pH of the ophthalmic composition may be adjusted using acids andbases, such as mineral acids, such as, but not limited to hydrochloricacid and bases such as sodium hydroxide.

The compositions of the present invention are also useful as packagingsolutions for packaging of ophthalmic devices and for storing suchophthalmic devices.

As used herein, “ophthalmic device” refers to an object that resides inor on the eye. These devices can provide optical correction or may becosmetic. Ophthalmic devices include but are not limited to soft contactlenses, intraocular lenses, overlay lenses, ocular inserts, punctualplugs, and optical inserts. The ophthalmic device may be a contact lens.Contact lenses useful with the compositions can be manufacturedemploying various conventional techniques, to yield a shaped articlehaving the desired posterior and anterior lens surfaces. Spincastingmethods are disclosed in U.S. Pat. Nos. 3,408,429 and 3,660,545; staticcasting methods are disclosed in U.S. Pat. Nos. 4,113,224, 4,197,266,and 5,271,875, each of which are herein incorporated by reference.Contact lens polymer materials useful for manufacturing suitable contactlenses include, but are not limited to, acofilcon A, alofilcon A,alphafilcon A, amifilcon A, astifilcon A, atalafilcon A, balafilcon A,bisfilcon A, bufilcon A, comfilcon, crofilcon A, cyclofilcon A,darfilcon A, deltafilcon A, delefilcon, deltafilcon B, dimefilcon A,drooxifilcon A, epsifilcon A, esterifilcon A, etafilcon A, fanfilcon A,focofilcon A, galyfilcon A, genfilcon A, govafilcon A, hefilcon A,hefilcon B, hefilcon D, hilafilcon A, hilafilcon B, hioxifilcon B,hioxifilcon C, hixoifilcon A, hydrofilcon A, lenefilcon A, licryfilconA, licryfilcon B, lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilconB, mafilcon A, mesifilcon A, methafilcon B, mipafilcon A, narafilcon A,narafilcon B, nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B,ocufilcon C, ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilconA, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, polymacon,riofilcon A, samfilcon A, senofilcon A, senofilcon C, silafilcon A,siloxyfilcon A, somofilcon A, stenfilcon A, tefilcon A, tetrafilcon A,trifilcon A, vasurfilcon, vifilcon, and xylofilcon A. Prefereably, thecontact lenses are manufactured using polymer materials selected from(or selected from the group consisting of) comfilcon, etafilcon A,galyfilcon A, senofilcon A, nelfilcon A, hilafilcon, tetrafilcon A,vasurfilcon, vifilcon, and polymacon.

Conventional hydrogel contact lenses do not contain silicone containingcomponents, and generally have higher water content, lower oxygenpermeability and moduli than silicone hydrogels. Conventional hydrogelsare prepared from monomeric mixtures predominantly containinghydrophilic monomers, such as 2-hydroxyethyl methacrylate (“HEMA”),N-vinyl pyrrolidone (“NVP”) or polyvinyl alcohols. U.S. Pat. Nos.4,495,313, 4,889,664 and 5,039,459 disclose the formation ofconventional hydrogels. Conventional hydrogels may be ionic or non-ionicand include polymacon, etafilcon, nelfilcon, ocufilcon lenefilcon andthe like. The oxygen permeability of these conventional hydrogelmaterials is typically below 20-30 barrers.

Silicon hydrogel formulations include balafilcon samfilcon, lotrafilconA and B, delfilcon, galyfilcon, senofilcon A, B and C, narafilcon,comfilcon, formofilcon, riofilcon, fanfilcon, stenfilcon, somofilcon,kalifilcon and the like. “Silicone hydrogels” refer to polymericnetworks made from at least one hydrophilic component and at least onesilicone-containing component. Silicone hydrogels may have moduli in therange of 60-200, 60-150 or 80-130 psi, water contents in the range of 20to 60%. Examples of silicone hydrogels include acquafilcon, asmofilcon,balafilcon, comfilcon, delefilcon, enfilcon, fanfilcon, formofilcon,galyfilcon, lotrafilcon, narafilcon, riofilcon, samfilcon, senofilcon,somofilcon, and stenfilcon, including all of their variants, as well assilicone hydrogels as prepared in U.S. Pat. Nos. 4,659,782, 4,659,783,5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,998,498, 6,087,415,5,760,100, 5,776,999, 5,789,461, 5,849,811, 5,965,631, 6,367,929,6,822,016, 6,867,245, 6,943,203, 7,247,692, 7,249,848, 7,553,880,7,666,921, 7,786,185, 7,956,131, 8,022,158, 8,273,802, 8,399,538,8,470,906, 8,450,387, 8,487,058, 8,507,577, 8,637,621, 8,703,891,8,937,110, 8,937,111, 8,940,812, 9,056,878, 9,057,821, 9,125,808,9,140,825, 9,156,934, 9,170,349, 9,244,196, 9,244,197, 9,260,544,9,297,928, 9,297,929 as well as WO 03/22321, WO 2008/061992, and US2010/0048847. These patents are hereby incorporated by reference intheir entireties.

The contact lens polymer material is preferably a silicone hydrogelpolymer. The silicone hydrogel may be selected from (or selected fromthe group consisting of) acquafilcon, asmofilcon, balafilcon A,comfilcon, delefilcon, enfilcon, galyfilcon, lotrafilcon, senofilcon,samfilcon, somofilcon, stenfilcon.

The compositions may also be useful for direct application to eye as awetting or rewetting eye drop for providing relief to eye discomfort(e.g., burning sensations relating to the eye or general eyeirritation).

The compositions described herein may be free of or substantially freeof preservatives. The term “preservative” means compounds havingantimicrobial properties. Examples of specific preservatives include,but are not limited to, 4-chlorocresol, 4-chloroxylenol, benzalkonium,benzalkonium chloride, benzoic acid, benzyl alcohol, chlorhexidine,chlorobutanol, imidurea, m-cresol, methylparaben, phenols 0.5%,phenoxyethanol, sorbate, propionic acid, propylparaben, sodium benzoate,sorbic acid, thimerosol, Stabilized Oxychloro Complex (SOC—99.5%chlorite, 0.5% chlorate, and with trace amounts of chlorine dioxide),polyquaternium compounds (such as polyquarternium-42 polyquarternium-1),perborate salts (e.g., sodium perborate, biguanide compounds (e gpolyhexamethylene biguanide or polyaminopropyl biguanide).

The term “substantially free” as related to preservatives means that thepreservative is present in the compositions of the present invention ata concentration of less than 2% (or about 2%), preferably less than 1.5%(or about 1.5%), and preferably less than 1% (or about 1%), preferablyless than 0.5% (or about 0.5%), preferably less than 0.1% (or about0.1%), preferably less than 0.05% (or about 0.05%), preferably less than0.01% (or about 0.01%), preferably less than 0.005% (or about 0.005%) byweight of the total composition. Preferably, the compositions of thepresent invention are free of preservatives.

As mentioned above, contact lenses can be immersed in a composition ofthe present invention and stored in a suitable packaging container,preferably, a packaging container for single contact lens unit.Generally, a packaging container for the storage of a contact lensincludes at least a sealing layer sealing the container containing anunused contact lens immersed in the composition of the presentinvention. The sealed container may be hermetically sealed packagingcontainer. The hermetically sealed packaging container may be a blisterpack in which a concave well containing a contact lens is covered by ametal or plastic sheet adapted for peeling in order to open theblister-pack. The sealed container may be formed from any suitable,generally inert packaging material providing a reasonable degree ofprotection to the lens. The packaging material may be formed of plasticmaterial such as polyalkylene, PVC, polyamide, glass, glassy polymersand the like.

Any water soluble, demulcent (or demulcent like—e.g., having demulcentproperties such as viscosity increasing capabilities) polymer may alsobe employed in the composition of this invention provided that it has no(or no substantial) detrimental effect on the contact lens being storedor on the wearer of the contact lens at the concentrations used in thecomposition of the present invention or on the eye (or on the regionaround the eye). Particularly useful components are those, which arewater soluble, for example, soluble at the concentrations used in thepresently useful liquid aqueous media. Suitable water soluble demulcentpolymers include, but are not limited to, demulcent polymers, such asblock copolymers of polyethyleneoxide (PEO) and polypropyleneoxide(PPO); polyvinyl alcohol, polyvinyl pyrrolidone; polyacrylic acid;polyethers such as polyethylene glycols (e.g., polyethylene glycol 300,polyethylene glycol 400) and polyethylene oxides; hyaluronic acid, andhyaluronic acid derivatives; chitosan; polysorbates such as polysorbate80, polysorbate 60 and polysorbate 40); dextrans such as dextran 70;cellulosic derivatives such as carboxy methyl cellulose methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, and methyl ethylcellulose; acyclic polyamides such as those having a weight averagemolecular weight of 2,500 to 1,800,000 Daltons as disclosed in U.S. Pat.No. 7,786,185 herein incorporated by reference in its entirety; salts ofany of the above and mixtures of any of the above. Preferably, the blockcopolymers of PEO and PPO include poloxamers and poloxamines, includingthose disclosed in U.S. Pat. No. 6,440,366, herein incorporated byreference in its entirety. Preferably, the water-soluble demulcentpolymer is selected from polyvinyl pyrrolidone, methyl ethyl cellulose,polyvinyl alcohol, polymethacrylic acid, carboxymethyl cellulose,glycerol, propylene glycol, 1,3-propanediol, polyethylene glycols, andmixtures thereof.

Lubricating agents may have molecular weights in excess of 100,000. Whenglycerol, propylene glycol and 1,3-propanediol are used as lubricatingagents, they may have molecular weights lower than 100,000.

When any water soluble polymer is used in the packing solutions of thepresent invention, it may be included and present in amounts up to about0.5, 1 or 2 weight % preferably between about 0.001 and about 2%,between about 0.005 and about 1%, between about 0.01 and about 0.5weight %, or between about 100 ppm and about 0.5 weight %, all basedupon the weight of total composition.

When any water soluble polymer is used in the direct application eyecare formulation or eye drop of the present invention, it may beincluded and present in amounts up to about 2, 5 or 10 weight %,preferably between about 0.001 and about 10%, between about 0.005 andabout 2%, between about 0.01 and about 0.5 weight %, or between about100 ppm and about 2 weight %, all based upon the weight of totalcomposition.

Without being limited by theory, it is believed that the water solubledemulcent polymer aids in preventing the ophthalmic device from stickingto its product packaging and may enhance the initial (and/or extended)comfort of the contact lens, packaged in the composition, when placed onthe eye after removal from the packaging.

The demulcent polymer may be a cellulosic derivative. The cellulosicderivative may be present at concentrations of from about 0.002 to about0.01, or preferably, from about 0.004 to about 0.006 by weight of thetotal composition of the present invention.

Various other materials may be included with the compositions describedherein.

In the case of compositions of the present invention for directapplication to the eye, surfactants may be included. Surfactantssuitable for such use include, but are not limited to, ionic andnonionic surfactants (though nonionic surfactants are preferred), RLM100, POE 20 cetylstearyl ethers such as Procol® CS20, poloxamers such asPluronic® F68, and block copolymers such aspoly(oxyethylene)-poly(oxybutylene) compounds set forth in U.S. PatentApplication Publication No. 2008/0138310 entitled “Use of PEO-PBO BlockCopolymers in Ophthalmic Compositions” filed Dec. 10, 2007 (whichpublication is herein incorporated by reference)

Surfactant may be present at concentrations of from about 0.01 to about3%, preferably from about 0.01 to about 1%, preferably, from about 0.02to about 0.5%, or preferably, from about 0.02 to about 0.1% by weight ofthe total composition of the present invention.

If desired, one or more additional components may be, optionally,included in the composition. Such optional component(s) are chosen toimpart or provide at least one beneficial or desired property to thecomposition. Such additional, but optional, components may be selectedfrom components that are conventionally used in ophthalmic device carecompositions Examples of such optional components include (or, areselected from or selected from the group consisting of) cleaning agents(for example in direct application eye drops or cleaning [or eye caresolution]), wetting agents, nutrient agents, therapeutic agent,sequestering agents, viscosity builders, contact lens conditioningagents, antioxidants, and the like and mixtures thereof. These optionalcomponents may each be included in the compositions in an amounteffective to impart or provide the beneficial or desired property to thecompositions such the beneficial or desired property is noticeable tothe user. For example, such optional components may be included in thecompositions in amounts similar to the amounts of such components usedin other eye or ophthalmic device care compositions products.

All components in the ophthalmic solution of the present inventionshould be water-soluble. As used herein, water soluble means that thecomponents, either alone or in combination with other components, do notform precipitates or gel particles visible to the human eye at theconcentrations selected and across the temperatures and pH regimescommon for manufacturing, sterilizing and storing the ophthalmicsolution

One or more therapeutic agent may also be incorporated into theophthalmic solution. A wide variety of therapeutic agents may be used,so long as the selected active agent is inert in the presence ofperoxides. Suitable therapeutic agents include those that treat ortarget any part of the ocular environment, including the anterior andposterior sections of the eye and include pharmaceutical agents,vitamins, nutraceuticals combinations thereof and the like. Suitableclasses of active agents include antihistamines, antibiotics, glaucomamedication, carbonic anhydrase inhibitors, anti-viral agents,anti-inflammatory agents, non-steroid anti-inflammatory drugs,antifungal drugs, anesthetic agents, miotics, mydriatics,immunosuppressive agents, antiparasitic drugs, anti-protozoal drugs,combinations thereof and the like. When active agents are included, theyare included in an amount sufficient to produce the desired therapeuticresult (a “therapeutically effective amount”).

Useful optional sequestering agents include, but are not limited to,disodium ethylene diamine tetraacetate (EDTA), alkali metalhexametaphosphate, citric acid, sodium citrate and the like and mixturesthereof.

Useful optional antioxidants include, but are not limited to, sodiummetabisulfite, sodium thiosulfate, N-acetylcysteine, butylatedhydroxyanisole, butylated hydroxytoluene and the like and mixturesthereof.

The method of packaging and storing a contact lens (or other ophthalmicdevice) includes at least incorporating the device into packaging wherethe device is immersed in the compositions described above. The methodmay include immersing the device in the composition prior to delivery tothe customer/wearer, directly following manufacture of the contact lens.Alternately, the incorporation and storing of the device in thecompositions (all in the packaging) may occur at an intermediate pointbefore delivery to the ultimate customer (wearer) but followingmanufacture and transportation of the device in a dry state, wherein thedry device is hydrated by immersing the device in the compositions.Consequently, a package for delivery to a customer may comprise a sealedcontainer containing one or more unused devices (e.g., contact lenses)immersed in the compositions.

In one preferred embodiment, the steps for packaging the device in thecomposition of the present invention include:

-   -   (1) molding a device (e.g., contact lens) in a mold comprising        at least a first and second mold portion,    -   (2) removing the device from the mold portions and removal of        unreacted monomer and processing agents    -   (3) introducing the composition and the device into the        packaging (or container), and    -   (4) sealing the packaging.

The method may also include the step of sterilizing the contents of thepackaging. Sterilization may take place prior to, or most convenientlyafter, sealing of the container and may be performed by any suitablemethod known in the art, e.g., by balanced autoclaving of the sealedcontainer at temperatures of about 120° C. or higher. The packaging maybe a plastic blister packaging (or package), including a recess forreceiving a device and the composition, where the recess is sealed withlidstock prior to sterilization of the package contents. The term“lidstock” as used herein means the foil laminate composite material,including the aluminum foil and the other layers of polymers, that isheat sealed to cover the concave side of the blister.

The following examples are provided to enable one skilled in the art topractice the compositions and are merely illustrative of the invention.The examples should not be read as limiting the scope of the inventionas defined in the claims.

EXAMPLES Example 1

Table 1 shows compositions (i.e., test Exp1-Exp5) useful as solutionsfor storing or as packaging solution for ophthalmic devices (e.g.,contact lenses) together with a control, each of which compositions canbe prepared using conventional mixing technology.

TABLE 1 Weight % (phosphates corrected for hydrates) Component EXP1 EXP2EXP3 EXP4 EXP5 Control Deionized 95.623 97.899 95.892 98.167 98.39 98.03Water Sodium 0.84 0.84 0.84 0.84 0.84 0.84 Chloride Boric Acid 0.4000.400 0.182 0.182 0 0.91 Sodium 0.092 0.092 0.042 0.042 0 0.21 BorateDecahydrate monobasic 1.047 0.262 1.047 0.262 0.262 0 sodium phosphatedibasic 1.987 0.497 1.987 0.497 0.497 0 sodium phosphate EDTA 0.0100.010 0.010 0.010 0.010 0.01

Once prepared, each of the compositions of Table 1 was poured from itsoriginal specimen cup containers and filter sterilized through a 0.22 μmmembrane using a 150-mL Analytical Filter Unit. The filtered individualcompositions were then aseptically transferred into new individualsterile specimen cups for storage and testing.

The following microorganisms were used to assess microbial activity:

Staphylococcus aureus (Quanti-Cult Plus™)—ATCC 6538 (Remel Inc.)

Escherichia coli (BioBall® Multishot 550)—NCTC 12923 (ATCC 8739)(bioMérieux)

Bacillus subtilis (Quanti-Cult Plus™)—ATCC 6633 (Remel Inc.)

Pseudomonas aeuroginosa ((Quanti-Cult Plus™))—ATCC 9027 (Remel Inc.)

Candida albicans ((Quanti-Cult Plus™))—ATCC 10231 (Remel Inc.)

Salmonella typhimurium (KWIK-STIK™)—ATCC 14028 (Microbiologics, Inc.)

Aspergillus brasiliensis ((Quanti-Cult Plus™))—ATCC 16404 (Remel Inc.)

Fusarium keratoplasticum (KWIK-STIK™)—ATCC 36031 (Microbiologics, Inc.)

For the Quanti-Cult Plus and BioBall Multishot microorganisms, asolution 1:1 (microorganism sample to composition) was prepared for eachcomposition of Table 1. An inoculum of 200 μl was used for spreadplating in duplicate.

For the remaining KWIK-STIK™ microorganisms (i.e., in swab/pelletpresentation), Microbiologics, Inc's instructions were followed forreconstitution. A stock solution was created using the disposableHemocytometer 2-Chip instructions (Bulldog Bio) for general methods.Based on results obtained, serial dilutions were performed to obtain acountable inoculum for each buffer. Inoculum volume used for spreadplating in duplicate was 100 μl.

Bacteria microorganisms were plated in tryptic soy agar (TSA) media andYeast and Fungi in Sabouraud dextrose agar (SDA) or SDA withchloramphenicol. TSA plates were incubated for 24-72 hrs. at 30-35° C.and SDA plates were incubated for 48 hrs. to 4 days at 20-25° C.

Quantitative analysis was performed on Day 0, 1 and 2. FIGS. 1-8summarize the results obtained:

The data in FIGS. 1-8 demonstrate that the compositions of Table 1provide bacteriostatic/fungistatic capability andbactericidal/fungicidal activity. FIG. 9 shows a comparison ofmicroorganism reduction percentage for each of compositions EXP1-EXP5 vsthe Control after 2 days. Compositions EXP1 and EXP2 show the mostequivalent reduction pattern vs the Control and showed stasis (i.e., noincrease from the initial count of inoculate microorganism) against allmicroorganisms after two days. However, composition EXP 2 shows the mostconsistent reduction % across all challenged microorganisms.

Example 2

The composition of Table 2 is useful as a solution for storing or aspackaging solution for ophthalmic devices (e.g., contact lenses) isprepared as described below using conventional mixing technology.

TABLE 2 Weight % (the balance is water) Component Boric acid 0.30%Sodium Chloride 0.55% Monobasic sodium  0.081% phosphate*H₂O Dibasicsodium phosphate*7H₂O 0.67% Disodium EDTA 0.01% MEC  0.005% Water98.384% Composition Properties pH 7.2*    Osmolality 288*      *Measuredin the composition absent the presence of MEC and EDTA - it beingrecognized that due the concentration of these components, suchcomponents alone or in combination would have minor impact on pH andosmolality relative to the remaining components.Once prepared, the composition of Table 2 was poured from their originalspecimen cup containers and filter sterilized through a 0.22 μm membraneusing a 250-mL Rapid Flow Filtration Unit. The filtered composition wasthen aseptically transferred into a sterile container for microbialgrowth testing on Pseudomonas aeuroginosa (Quanti Cult plus)—usingPseudomonas aeuroginosa ATTC culture type no. 9027).

P. aeruginosa (PA) Quanti-Cult plus was resuspended followingmanufacturers' instructions and an approximately 500 μL aliquot wasspread plated onto two separate tryptic soy agar (TSA) plates. Theplates were incubated at 30-35° C. for 2 days. An inoculating loop wasused to resuspend the PA from the TSA plate surface in OmniPur WFIQuality Water, Sterile Filtered, Calbiochem (WFI).

The suspension was aseptically transferred with a sterile pipette into a50 mL centrifuge tube.

The PA suspension was serially diluted with WFI quality sterile waterand a hemocytometer (Disposable Hemocytometer, Bulldog Bio) was used toobtain a 1:1000 dilution containing a target population count ofapproximately 1.0×10⁷ cells/mL.

Ten μL aliquot of the 1:1000 PA dilution was inoculated into 40 mL ofthe composition of Table 1 and a 1×PBS control solution to obtain astarting PA target population count of approximately 2500 CFU/mL.(PBS=AccuGENE 1× Phosphate Buffered Saline, 1.7 mM KH₂PO₄, 5 mM Na₂HPO₄,150 mM NaCl, pH 7.4, Cat. No. 51225, LONZA). 100 μL of the PBS controlsolution was plated in triplicate onto TSA plates and incubated at30-35° C. to determine the Day 0 PA delivery counts.

The PA inoculated composition of Table 2 and PBS control were stored atroom temperature and at Day 1, Day 2 and Day 3 samples were spreadplated (100-300 μL aliquots) in triplicate onto TSA. The plates werethen incubated at 30-35° C. to quantitate the PA population countsfollowing room temperature storage. The results for the composition inTable 1 is represented as “Exp. 7” in FIGS. 10-12.

As shown in FIGS. 10-12, the composition of Table 2 (shown as “Exp7”)caused a greater reduction in PA population counts compared to the PBScontrol and, accordingly, provide the desired bacteriostatic properties.The reduction in PA population provided further evidence of preventionof increase from initial PA population count—or that bacteriostasis wasachieved.

Example 3

The composition of Table 3 is useful as a solution for storing or aspackaging solution for ophthalmic devices (e.g., contact lenses) isprepared as described below using conventional mixing technology.

TABLE 3 Weight % (the balance is water) Component Boric acid 0.29%Sodium Chloride 0.60% Monobasic sodium 0.081% phosphate*H₂O Dibasicsodium phosphate*7H₂O 0.67% Disodium EDTA 0.01% MEC 0.005% Water 98.394%Composition Properties pH 7.2 Osmolarity 308

Preferred Embodiments

-   1. A composition, comprising:    -   a. from about 0.1% w/v to less than or equal to about 0.80% w/v        of a borate compound;    -   b. from about 0.3% w/v to about 0.9% w/v of a phosphate        compound; and    -   c. ophthalmologically acceptable carrier    -   wherein the concentration of the phosphate compound is at least        about 1.5 times the amount of the borate compound on weight        basis.-   2. The composition of embodiment 1 wherein the composition comprises    from about 0.2% w/v to less than or equal to 0.7% w/v of a borate    compound.-   3. The composition of embodiments 1 and/or 2 wherein the composition    comprises from about 0.25% w/v to less than or equal to 0.45% w/v of    a borate compound.-   4. The composition of any of the preceding embodiments wherein the    composition comprises from about 0.25% w/v to less than or equal to    0.4% w/v of a borate compound.-   5. The composition of any of the preceding embodiments wherein the    composition comprises from about 0.4% w/v to about 0.85% w/v of a    phosphate compound.-   6. The composition of any of the preceding embodiments wherein the    composition comprises from about 0.5% w/v to about 0.8% w/v of a    phosphate compound.-   7. The composition of any of the preceding embodiments wherein the    phosphate compound is at least about 2.5 times the amount of the    borate compound on a weight basis.-   8. The composition of any of the preceding embodiments wherein the    ratio of the phosphate compound to the boric acid compound is from    about 1.5:1 to about 3:1 on a weight basis.-   9. The composition of any of the preceding embodiments wherein the    ratio of the phosphate compound to the boric acid compound is from    about 2:1 to about 3:1 on a weight basis-   10. The composition of any of the preceding embodiments wherein the    composition is substantially free of preservatives.-   11. The composition of any of the preceding embodiments wherein the    composition is free of preservatives.-   12. The composition of any of the preceding embodiments further    comprising a demulcent polymer.-   13. The composition of any of the preceding embodiments wherein the    demulcent polymer is selected from block copolymers of    polyethyleneoxide (PEO) and polypropyleneoxide (PPO), polyvinyl    alcohol, polyvinyl pyrrolidone, polyacrylic acid, polyethers,    hyaluronic acid and hyaluronic acid derivatives, chitosan,    polysorbates, dextrans, cellulosic derivatives, acyclic polyamides,    salts thereof and mixtures thereof-   14. The composition of any of the preceding embodiments further    comprising additional components selected from cleaning agents,    wetting agents, nutrient agents, therapeutic agent, sequestering    agents, viscosity builders, contact lens conditioning agents,    antioxidants, and the like and mixtures thereof.

What is claimed is:
 1. A composition, comprising: a. from about 0.1% w/vto less than or equal to about 0.80% w/v of a borate compound; b. fromabout 0.3% w/v to about 0.9% w/v of a phosphate compound; and c.ophthalmologically acceptable carrier wherein the concentration of thephosphate compound is at least about 1.5 times the amount of the boratecompound on weight basis.
 2. The composition of claim 1 wherein thecomposition comprises from about 0.2% w/v to less than or equal to 0.7%w/v of a borate compound.
 3. The composition of claim 2 wherein thecomposition comprises from about 0.25% w/v to less than or equal to0.45% w/v of a borate compound.
 4. The composition of claim 3 whereinthe composition comprises from about 0.25% w/v to less than or equal to0.4% w/v of a borate compound.
 5. The composition of claim 1 wherein thecomposition comprises from about 0.4% w/v to about 0.85% w/v of aphosphate compound.
 6. The composition of claim 5 wherein thecomposition comprises from about 0.5% w/v to about 0.8% w/v of aphosphate compound.
 7. The composition of claim 1 wherein the phosphatecompound is at least about 2.5 times the amount of the borate compoundon a weight basis.
 8. The composition of claim 7 wherein the ratio ofthe phosphate compound to the boric acid compound is from about 1.5:1 toabout 3:1 on a weight basis.
 9. The composition of claim 7 wherein theratio of the phosphate compound to the boric acid compound is from about2:1 to about 3:1 on a weight basis
 10. The composition of claim 1wherein the composition is substantially free of preservatives.
 11. Thecomposition of claim 10 wherein the composition is free ofpreservatives.
 12. The composition of claim 1 further comprising ademulcent polymer.
 13. The composition of claim 12, wherein thedemulcent polymer is selected from block copolymers of polyethyleneoxide(PEO) and polypropyleneoxide (PPO), polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, polyethers, hyaluronic acid andhyaluronic acid derivatives, chitosan, polysorbates, dextrans,cellulosic derivatives, acyclic polyamides, salts thereof and mixturethereof.
 14. The composition of claim 1 further comprising additionalcomponents selected from cleaning agents, wetting agents, nutrientagents, therapeutic agent, sequestering agents, viscosity builders,contact lens conditioning agents, antioxidants, and the like andmixtures thereof.